About 250,000 Americans suffer from spinal cord injury (SCI). SCI results in a loss of the rapid and modulatory descending inputs from the brain to the spinal Central Pattern Generator (CPG) networks that organize and drive locomotion. One consequence of this loss is that the spinal neurons undergo plastic changes that can lead to dysfunction, such as spasticity. While changes in motoneuron properties have after SCI have been measured, the effects of SCI on identified CPG interneurons have not yet been studied. The major hypothesis of this proposal is that the loss of descending fast and modulatory inputs to the CPG after SCI causes slow compensatory changes in the locomotor CPG network, due to changes in the intrinsic properties of component neurons and/or their synaptic interactions. Further, these changes may vary between different neuron types. This hypothesis will be tested in the adult mouse spinal cord, where genetic tools have been developed to identify and fluorescently label different classes of interneurons. We have developed a perforated patch method for stable recordings from adult spinal interneurons to monitor neuronal properties and their synaptic connections in spinal cord slice preparations. This method will be used to record activity in a set of genetically identified interneurons that participate in the mouse hindlimb locomotor CPG, and to compare their properties in control animals and after SCI. The proposal has three specific aims. First, study the effects of SCI on the intrinsic electrophysiological properties of genetically identified CPG interneurons, and their sensitivity to neuromodulators such as serotonin. Second, examine at the biophysical and molecular level changes in expression of ion channels and receptors in identified spinal neurons after SCI, which cause the changes in their firing properties. Third, examine changes in synaptic drive and its plasticity between identified spinal neurons after SCI. These experiments should yield valuable information on the consequences of SCI for neurons and networks below a lesion that are not themselves damaged by the injury, but change their properties as a consequence of the loss of normal inputs from the brain. They will provide specific cellular mechanisms as potential targets for future treatment to maintain the locomotor CPG in a functional state during the time for repair of descending inputs to assist in the restoration of locomotion.

Public Health Relevance

This work will address the consequences of spinal cord injury for the spinal neurons and connections that normally organize and drive locomotion. It will identify changes in neuronal activity and synaptic interactions that may disturb normal locomotor network function. These changes will be targets for future treatments to maintain network function during the eventual period of recovery from spinal cord damage.